Herpesvirus

Herpesviruses are large DNA viruses whose genomes consist of a large linear double-stranded DNA molecule, 125 kbp to 229 kbp in length. Their hosts range from lower vertebrates to humans. At present, approximately 100 herpesviruses have been isolated and at least partially characterized. In humans, five viruses [herpes simplex virus 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV,( human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV)] have been identified as members of the herpesvirus family, Herpesviridae. In the past decade, however, three new herpesviruses, namely, human herpesvirus 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), were isolated from healthy people and AIDS patients. These human herpesviruses are responsible for a wide variety of diseases.

 Although herpesviruses share common features in their structure, gene organization, replication style, and so forth, the family Herpesviridae is further divided into three subfamilies, Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. Alphaherpesvirinae includes HSV-1, HSV-2, VZV, pseudorabies virus, equine herpesvirus 1 (EHV-1), and so on. They have a relatively short replication cycle, induce cytocidal damage in infected cells, and establish latency primarily in sensory ganglia. Betaherpesvirinae includes HCMV, HHV-6, HHV-7, and so on, and is characterized by its restricted host range, long replication cycle, and slow spread of infection from  cell to cell in culture. They can establish latency in lymphoreticular cells, secretory glands, kidneys, and other tissues. Gammaherpesvirinae contains EBV, HHV-8 (Kaposi's sarcoma-associated herpesvirus), herpesvirus saimiri (HVS), and so on. They replicate in lymphoid cells, and latency is frequently demonstrated in lymphoid tissue. A most important feature of this subfamily is that some are associated with naturally occurring malignant tumors.

 The virions of herpesviruses consist of four morphological elements: an inner core, an icosahedral capsid with 162  capsomers, a surrounding amorphous layer, known as the tegument, and an envelope containing a number of glycoproteins. The tegument of the HSV virion is known to contain about 20 distinct structural proteins, some of which have important regulatory functions for the initiation of viral replication. The genomes of eight human herpesviruses have been entirely sequenced, and the complete DNA sequences are also available for several animal herpesviruses, including EHV-1, EHV-2, HVS, and mouse CMV. Although the number of viral genes encoded in the genomes varies, a set of approximately 40  genes is conserved in all herpesviruses. These encode capsid proteins, envelope glycoproteins, proteins involved in DNA cleavage/packaging, and enzymes such as DNA polymerase, DNA helicase, DNA primase, uracil-DNA glycosylase, dUTPase, ribonucleotide reductase, and protein kinase. The herpesvirus genomes contain a number of accessory genes that are dispensable for viral replication in cell culture. For example, 45 of 84 HSV genes have been shown to be nonessential. These accessory gene products are supposed, however, to be important for viral growth and spread in their natural hosts.

 The principal strategy of herpesvirus replication is similar in all of them and can be summarized as follows: (i) Fusion of the virion envelope with the plasma membrane occurs at the cell surface in a pH-independent manner; (ii) viral capsids with a portion of the tegument are transported to a nuclear pore, where viral DNA is released into the nucleus, circularized, and then transcribed by cellular RNA polymerase II; (iii) viral gene expression is coordinately regulated and sequentially ordered in a cascade fashion; (iv) viral DNA replicates by a rolling circle mechanism, and unit-length viral DNA is cleaved from newly synthesized concatemers and packaged into preformed empty capsids;)v) full capsids pass through the inner and outer membranes of the nuclear envelope by budding and reenvelopment and associate with tegument proteins in the perinuclear region; (vi) enveloped virions accumulate in the endoplasmic reticulum and then mature in the Golgi apparatus; and finally, (vii( mature virions are released into the extracellular space by exocytosis.

All herpesviruses have the ability to persist in their natural hosts throughout life. During latency, the viral genomes are present in the form of an episome in the nucleus, and only a small subset of viral genes is transcribed. The synthesis of specific viral proteins appears to be essential for some herpesviruses to maintain latency, but not for others. Various stimuli, such as stress and immunosuppression, induce reactivation, which triggers viral replication and shedding of infectious virus. The molecular mechanism of herpesvirus reactivation remains to be elucidated.

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